In prior studies, we demonstrated that transplantation of major histocompatibility complex (MHC)-mismatched purified hematopoietic stem cells (HSCs) can block diabetes pathogenesis in pre-diabetic NOD mice, and lead to long-term cures of overtly hyperglycemic NOD mice when HSCs were co-transplanted with donor matched islets. We subsequently observed that hematopoietic cell grafts from MHC-matched donors could also block diabetes pathogenesis. The latter data suggest that non-MHC genes expressed in transferred hematolymphoid cells can block diabetes pathogenesis. The identity of these protective genes is not known. Based upon the efforts of many investigators, diabetes resistant NOD mice have been generated that have a single genetic alteration at the MHC regions or that are congenic for background resistance genes derived from C57BL mice. The hypothesis tested in this project is that by using diabetes resistant NOD transgenic or congenic donors, we will be able to identify the protective genes expressed in hematopoietic cells. Our approach is to transplant hematopoietic cell grafts of defined cell type from these donors, and assess diabetes outcome. The value of identifying molecules specific to hematopoietic cells that are capable of blocking diabetes pathogenesis is that such knowledge may serve to: [unreadable] [unreadable] Further define the mechanisms by which autoimmunity is perpetuated; and [unreadable] Open the possibility that HSCs may be genetically manipulated so that manipulated autologous HSCs rather than fully allogeneic HSCs can be used to block autoimmune pathogenesis. [unreadable] [unreadable] Since co-transplantation of insulin producing tissue is necessary to obtain cure of overtly diabetic humans and mice, this project will also study co-transplantation of hematopoietic cells from the congenic or transgenic donors in combination with islets. The adult islet sources studied will be from donor matched, NOD.SCID mice or third party islets. We will further determine if insulin-producing cell clusters derived from embryonic stem cells can confer benefits similar to adult islets when transplanted in conjunction with hematopoietic cells. [unreadable] [unreadable]